Perturbations of homocysteine metabolism are associated with increased risk for cardiovascular disease, stroke, dementia, and depression, among other major diseases. To assess the relationship between hypohomocysteinemia (HH) and idiopathic peripheral neuropathy (IPN), a retrospective review of 37,442 patients from a tertiary medical clinic was performed. Of patients with HH, 5.9% had IPN versus 0.6% of patients without IPN. Overall, 41% of patients with HH had IPN. These observations indicate that although HH is uncommon in the general population, there is a striking relationship between HH and the incidence of IPN. This article discusses the clinical ramifications of these findings.